Using AHRQ’s Evidence-Based Reports to Improve Managed Care Pharmacy Practice: Oral Antidiabetic Agents

Managed care pharmacists are faced daily with choices regarding how to deliver the best care with finite resources. Whether it is through encouraging appropriate utilization of medications via formulary management and drug utilization evaluation or through chronic diseasemanagement programs, pharmacists are guiding patient care with effectiveness, quality, and an eye toward value. It is with these goals in mind that pharmacists can benefit from the research produced by the Agency for Healthcare Research and Quality (AHRQ).

this amount, $300 million were allocated specifically to AHRQ for CER. With this additional funding, AHRQ contracted with evidence-based practice centers (EPCs) to conduct evidence reviews and to identify gaps in the evidence in 14 major areas: (1) arthritis and nontraumatic joint disorders; (2) cancer; (3) cardiovascular disease; (4) dementia; (5) depression and other mental health disorders; (6) developmental delays, attentiondeficit hyperactivity disorder, and autism; (7) diabetes mellitus; (8) functional limitations and disability; (9) infectious diseases; (10) obesity; (11) peptic ulcer disease and dyspepsia; (12) pregnancy; (13) pulmonary disease/asthma; and (14) substance abuse. 7,8 More information regarding AHRQ's research that is being funded by ARRA is available on AHRQ's website. 9 In 2010, the PPACA authorized the creation of a nonprofit corporation, the Patient-Centered Outcomes Research Institute (PCORI). 5 This institute is charged with assisting patients and health care decision makers to make more informed decisions by improving the quality and relevance of clinical evidence. PCORI will also contract with AHRQ, thus again expanding AHRQ's research capabilities in CER. Of note, both AHRQ and PCORI make efforts to minimize the impact of potential conflicts of interest arising from key stakeholders involved in their research agenda. Stakeholders, such as executive staff, EPC members, technical experts, and advisory experts, are required to disclose annually any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Moreover, those who are invited to serve as EPC report peer reviewers and editors are not permitted to have any financial conflict of interest greater than $10,000. 5,[10][11][12][13]

AHRQ and the Evidence-Based Review Process
One way in which ARHQ performs CER is via systematic reviews of the scientific literature. Towards this end, AHRQ in 1997 established EPCs in the United States and Canada to synthesize existing scientific literature about important health care topics and promote evidence-based practice. These EPCs utilize systematic review methodology to develop evidence reports on clinical, social science/behavioral, economic, and other health care organization and delivery topics, focusing on topics that are common, expensive, and/or significant for the Medicare and Medicaid populations. A brief summary of AHRQ's review process is presented below, and more detailed explanations of AHRQ's review methodology are available on AHRQ's website and in a peer-reviewed journal article by Chou et al (2010). 14,15 nitude of effect, and plausible confounding that would decrease observed effect) to arrive at 1 of 4 strength-of-evidence levels: high, moderate, low, or insufficient. The EPCs are given freedom to determine how the domains are combined to arrive at a strength-of-evidence grade so long as several principles are followed: (1) the EPC has an a priori plan for combining the domains, (2) risk of bias is considered an essential component of the assessment, and (3) each of the 4 major domains is assessed. As of March 2011, AHRQ's 14 EPCs have completed more than 190 evidence reports, and 78 more reports are currently in production (Table 1). 18

March 2011 Update on the Comparative Effectiveness and Safety of Oral Diabetes Medications
In March 2011, AHRQ updated its 2007 systematic review of the comparative effectiveness and safety of oral diabetes medications for adults with type 2 diabetes. 6 Based on stakeholder input, AHRQ has structured the review around addressing 4 key questions for adults aged 18 years or older with type 2 diabetes mellitus: (1) What is the comparative effectiveness of antidiabetic agents for intermediate outcomes? (2) What is the comparative effectiveness of antidiabetic agents for long-term outcomes? (3) What is the comparative safety of antidiabetic agents? (4) Do the safety and effectiveness of antidiabetic agents differ across patient subgroups?
In particular, the review aimed to contribute to our current understanding of the medical treatment of diabetes by focusing on head-to-head comparisons between medications. Head-tohead comparisons are particularly relevant to clinicians, such as medication therapy management pharmacists, because they directly compare the safety and effectiveness profiles of medications and thus help clinicians choose the most appropriate medications for their patients. Moreover, the report assessed the comparative safety and effectiveness of combinations of medications. These comparisons are becoming increasingly pertinent because the estimated percentage of U.S. patients with diabetes taking 2 or more antidiabetic medications has risen from 33.6% in 1999-2000 to 49.5% in 2005-2006. 19 The AHRQ review was published as a full report on AHRQ's website and as an article in a peer-reviewed journal . 6,20 Short, plain-language guides with versions tailored to clinicians or to patients are also available on AHRQ's website. 21,22 The following is a selection of some of the key findings that were deemed by the author of this commentary to be most clinically relevant (Table 2).

Key Question 1: Comparative Effectiveness of Antidiabetic Agents for Intermediate Outcomes
Reduction in A1c. The report found moderate to high levels of evidence to show that oral medications (with the exception of dipeptidyl peptidase-4 [DPP-4] inhibitors) were An AHRQ review is developed in 4 major steps: (1) formulating the problem; (2) systematically searching the medical literature for relevant research studies to address the study problem; (3) assessing the strength of evidence of the results as it applies to the research question and when appropriate, conducting a meta-analysis to summarize results from multiple studies; and (4) presenting review results in the most transparent and balanced manner to facilitate decision making. As stakeholders, pharmacists are also encouraged to nominate topics, to comment on study protocols, and to review draft reports.
AHRQ first develops study topics through iterative input from the public, clinicians, and content experts by soliciting stakeholder topic nominations on its website. 16 AHRQ then engages stakeholders to refine a set of key questions to guide the scope of the review.
The evidence synthesis draws from experimental as well as observational studies. This perspective recognizes differences in the information that can be provided by each type of study. Whereas the highly controlled criteria and procedures used in an interventional, randomized controlled trial (RCT) may minimize bias and provide the best evidence of the efficacy of a treatment, the detailed criteria and experimental conditions may themselves prevent conclusions from being drawn regarding a treatment's effectiveness and safety in daily practice. Moreover, due to the cost of interventional trials, it is rare to have RCT information that can answer questions regarding long-term or rare adverse effects. Thus, AHRQ's evidence synthesis makes use of observational studies to address the evidence gaps found in the RCTs, while recognizing the potential risk of bias in observational studies.
In assessing the strength of evidence of CER conclusions, EPCs use an approach modified from the Grading of Recommendations Assessment, Development and Evaluation (GRADE) workgroup approach to grade the quality of evidence. 14,17 Readers familiar with GRADE may notice that an AHRQ review does not present a "strength of recommendation" rating, (i.e., a rating of the reviewers' confidence that the intervention being evaluated does more good than harm), which GRADE employs in addition to its "quality of evidence" rating. This is because an AHRQ review is intended to be used by a variety of decision makers with diverse perspectives and needs. Hence, the review strives primarily to inform decision makers regarding the strength of evidence and does not make explicit recommendations.
For each major outcome or comparison of interest, the EPCs assess at least the 4 following domains: (1) the risk of bias (i.e., internal validity), (2) consistency (i.e., consistent effect sizes across studies), (3) directness (i.e., degree to which the evidence links the intervention[s] to the relevant health outcome), and (4) precision (i.e., degree of confidence surrounding an effect estimate). The EPCs then consider these and additional optional domains (including dose-response association, mag- Weight Gain. Since obesity is commonly associated with insulin resistance, the comparative weight gain associated with the use of antidiabetic medications should be considered. Based on trials that generally were less than 1 year in length, there were high levels of evidence indicating that TZD monotherapy and sulfonylurea monotherapy were associated with more weight gain compared with metformin monotherapy (mean 2.6 kilograms [kg], 95% CI = 1.2-4.1 kg, and mean 2.7 kg, 95% CI = 1.9-3.5 kg, respectively). [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Moreover, there was a moderate level of evidence from multiple short-term (24-week) studies suggesting that metformin monotherapy was associated with greater weight loss than DPP-4 inhibitor monotherapy (mean 1.4 kg, 95% CI = 1.0-1.8 kg). There was also a low level of evidence suggesting that a sulfonylurea as monotherapy was associated with less weight gain than a TZD as monotherapy (mean 1.2 kg, 95% CI = 0.6-1.9 kg) and moderate levels of evidence suggesting that a sulfonylurea in combination with metformin was associated with less weight gain than a TZD in combination with metformin (mean 0.9 kg, 95% CI = 0.4-1.3 kg).

Key Question 2: Comparative Effectiveness of Antidiabetic Agents for Long-Term Outcomes Cardiovascular/Cerebrovascular Morbidity and Cardiovascular Mortality.
In assessing cardiovascular/cerebrovascular morbidity or cardiovascular mortality as endpoints, the majority of studies possessed low strength of evidence because of short duration (less than 1 year) and few events. Because the majority of studies used an observational study design and 1 study out of 7 produced contrary results, there was a low strength of evidence suggesting that metformin might be associated with a slightly lower risk of cardiovascular mortality compared with a sulfonylurea. There was also low strength of evidence (due to high imprecision and moderate risk of bias) suggesting that the risk of cardiovascular mortality was similar between metformin and TZDs as monotherapy. 6 In assessing the risk of cardiovascular/cerebrovascular morbidity, there were inconclusive results (due to conflicting evidence) comparing metformin to sulfonylureas in monotherapy, with some studies showing lowered risk, others showing elevated risk, and others showing similar risk. There were also inconclusive results (due to high imprecision and inconsistency in direction of findings) when comparing metformin and TZDs as monotherapy; some studies reported elevated risk of myocardial infarction (MI), angina pectoris, stroke, or transient ischemic attack associated with TZDs, whereas others found no significant difference. There was also a nonstatistically significant trend with high imprecision suggesting that metformin alone might be associated with lower risk of combined fatal and nonfatal ischemic heart disease than a combination of metformin and rosiglitazone with an odds ratio (OR) of 0.463 (95% CI = 0.17-1.10). 6 Retinopathy. The report did not find any studies that assessed diabetic retinopathy.

Nephropathy.
There was a moderate level of evidence that pioglitazone was better at lowering the urinary albumin-tocreatinine ratio, which is suggestive of reduced nephropathy. The evidence was based on the findings of 2 trials (n = 1,176 and n = 639) that relative to metformin, patients taking pioglitazone had a statistically significant decline in urinary albumin-to-creatinine ratio (15%, P = 0.002, and 19%, P = 0.017, respectively). 38,39 Urinary albumin-to-creatinine ratio remained unchanged in patients on metformin.
Neuropathy. The report found insufficient evidence to compare effects of the antidiabetic medications on neuropathy.

Key Question 3: Comparative Safety of Antidiabetic Agents
Heart Failure. There was low strength of evidence suggesting that TZD monotherapy was associated with greater risk of heart failure compared with metformin monotherapy, although none of the 7 studies reported reached statistical significance. 6 There was moderate strength of evidence indicating that TZD monotherapy was associated with greater risk of heart failure when compared with sulfonylurea monotherapy. Although only 1 of 8 individual observational or interventional studies reached statistical significance, a meta-analysis of the 4 interventional trials was suggestive of clinically significant risk of heart failure (relative risk = 1.68, 95% CI = 0.99-2.85). 6 Moreover, there was low strength of evidence (1 out of 4 observational studies) indicating that pioglitazone monotherapy was associated with a statistically significantly decreased risk of heart failure when compared with rosiglitazone monotherapy (hazard ratio [HR] = 0.77, 95% CI = 0.69-0.87). 40 Hypoglycemia. Hypoglycemia is an important side effect because it is associated with confusion, dizziness, and syncope. Severe hypoglycemia may even cause seizures and/or Using AHRQ's Evidence-Based Reports to Improve Managed Care Pharmacy Practice: Oral Antidiabetic Agents

Findings
Strength of Evidence a Glycemic control On average, many of the single agents reduce HbA1c levels by 1 percentage point.
Moderate to High On average, 2-drug combination therapies reduce HbA1c about 1 percentage point more than monotherapies.
Moderate to High

Weight gain
Metformin monotherapy was associated with less weight gain when compared with other monotherapies or 2-drug combinations. Moderate to High The combination of metformin with sulfonylurea was associated with less weight gain than were 2-drug combinations with TZDs. Moderate

Risk of adverse effects
Sulfonylureas were more likely to cause mild to moderate hypoglycemia than monotherapy with either metformin or TZDs. Moderate to High TZDs are associated with a higher risk of congestive heart failure when compared with sulfonylurea.
Moderate TZDs alone or in combination are associated with a higher risk of hip and nonhip fractures when compared with other agents.
High agents. Moreover, metformin in combination with a sulfonylurea is associated with less weight gain than metformin in combination with a TZD.
In terms of long-term outcomes, the majority of results for cardiovascular/cerebrovascular morbidity and cardiovascular mortality were either of low strength of evidence or inconclusive. Metformin was associated with a slightly lower risk of cardiovascular mortality than sulfonylureas. The cardiovascular/ cerebrovascular morbidity and cardiovascular mortality results comparing metformin and TZDs were inconclusive.
This finding regarding TZDs differs from that of a metaanalysis conducted by Nissen and Wolski (2010), which showed a statistically significantly elevated odds of MI for rosiglitazone compared with control antidiabetic medications (OR = 1.28, 95% CI = 1.02-1.63, P = 0.04) but not death from cardiovascular causes (OR = 1.03, 95% CI = 0.78-1.36, P = 0.86). 20, 43 Nissen and Wolski performed an additional analysis excluding the open-label, randomized noninferiority trial RECORD, which was criticized for having insufficient statistical power to detect an increased risk of ischemic cardiovascular events. 43 This alternate analysis yielded a larger OR for MI (OR = 1.39, 95% CI = 1.02-1.89, P = 0.04) and a larger but still nonsignificant OR for cardiovascular mortality (OR = 1.46, 95% CI = 0.92-2.33, P = 0.11). The disparity may have been a consequence of the different inclusion criteria used in the 2 analyses. The AHRQ analysis was limited to active comparator studies of patients with type 2 diabetes, whereas Nissen and Wolski included placebo-controlled trials of people with type 2 diabetes or other chronic diseases.
In assessing the comparative safety of the medications, there is evidence suggesting that TZDs are associated with greater risks for heart failure than sulfonylureas. TZDs are also associated with more bone fractures than other agents. Moreover, sulfonylureas in monotherapy and sulfonylureas in combination with metformin were associated with greater risks for hypoglycemia than TZDs in monotherapy and TZDs in combination with metformin, respectively.
In July 2010, an FDA advisory committee convened to deliberate on the safety of rosiglitazone. 44 After acknowledging the weak and potentially biased evidentiary base, members of the committee voted 18-to-6 that rosiglitazone poses "significant safety concerns" for ischemic cardiovascular events relative to non-TZD antidiabetic agents but also voted 20-to-12 to keep the drug on the market (with some recommending additional restrictions and stronger warnings). Consequently, the U.S. Food and Drug Administration (FDA) implemented a risk evaluation and mitigation strategy (REMS) restricting the use of rosiglitazone to patients and providers who acknowledge the potentially increased risk of MI associated with the use of rosiglitazone. 45 Given the FDA REMS restriction and enhanced warning regarding MI, it is prudent to carefully assess the cardiovascular risk on an individual basis prior to initiating death. There was high strength of evidence indicating that sulfonylureas as monotherapy were associated with greater risks of hypoglycemia than TZDs (OR = 3.9, 95% CI = 3.1-4.9) or metformin (OR = 4.6, 95% CI = 3.2-6.5). There was also high strength of evidence to conclude that metformin in combination with a sulfonylurea poses a greater than 5-fold risk of hypoglycemia than metformin in combination with a TZD. 6 Bone Fractures. The AHRQ report found high strength of evidence indicating that TZDs as monotherapy or in combination were associated with increased risk of bone fractures compared with metformin alone or in combination with a sulfonylurea. A subgroup analysis of all women in 1 large RCT found an HR of 1.81 (95% CI = 1.17-2.80) for risk of fracture for rosiglitazone versus metformin. 41 This finding carries important clinical ramifications, as elderly women are already at greater risk for bone fractures than the general population.

Key Question 4: Safety and Effectiveness Across Subgroups
There were few studies with sufficient statistical power to assess comparative safety and effectiveness across subgroups. Hence, it is unclear whether particular agents should be favored in various subgroups. However, 2 studies suggested that women taking rosiglitazone have a greater fracture risk than men taking rosiglitazone. A retrospective analysis of the A Diabetes Outcome Progression Trial (ADOPT) indicated that women on rosiglitazone had a higher fracture risk relative to metformin or glyburide (HRs of 1.57 and 1.61, respectively). 41 The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study found that the fracture risk associated with using a combination of rosiglitazone plus metformin or sulfonylurea, compared with metformin plus sulfonylurea, was higher for women than for men (relative risk [RR] = 1.82, 95% CI = 1.37-2.41 and RR = 1.23, 95% CI = 0.85-1.77, respectively). 42

■■ Discussion
This summary of AHRQ's 2011 update on the comparative effectiveness and safety of oral antidiabetes medications was written not only to provide pharmacists with up-to-date information relevant to the practice of managed care pharmacy but also to show how AHRQ's process in conducting systematic reviews and the reviews themselves can be useful for managed care pharmacists in improving patient care.
The results from this report indicate that in terms of intermediate outcomes, most antidiabetic agents were equivalently efficacious in glycemic control but not equivalent in weight gain ( Table 2). On average, most antidiabetic agents in monotherapy were able to decrease A1c by 1 percentage point. Combination therapy with 2 drugs was generally able to decrease A1c by another percentage point relative to monotherapy. Metformin was associated with less weight gain compared with other rosglitazone therapy.
Based on the above information, the choice of antidiabetic agent should not be based solely upon glycemic control but should also account for other intermediate and long-term outcomes, safety, and costs (the AHRQ report also lists the average wholesale price of the medications evaluated). 6,46 Hence, there is some evidence that managed care pharmacists when developing drug formularies should (a) consider a tiered system in which older, less costly agents with favorable effectiveness and safety profiles, such as metformin, are considered for first-line therapy and (b) restrict the use of agents such as rosiglitazone, for which the benefit risk profile is comparatively less favorable for the majority of patients.
Moreover, the review can be useful to managed care pharmacists by serving as an important resource for the production of drug evaluation monographs. Since the purpose of a drug monograph is to systematically determine the place in therapy of a medication or class of medications, and AHRQ's reviews have the purpose of systematically comparing the effectiveness and safety of medications, the 2 processes are highly congruent. Thorough literature searches for drug monograph preparation should include a search for AHRQ systematic reviews. Indeed, the AMCP eDossier system provides a link to the AHRQ systematic review repository. 47 AHRQ systematic reviews are an important tool available to managed care pharmacists in optimizing the effectiveness, quality, and value of the pharmacy benefit. Managed care pharmacists are strongly encouraged to take advantage of this practical and relevant resource.